5-HT is a pivotal CNS regulatory molecule of food intake, energy usage and deposition. 5-HTergic drugs have long been used in the treatment of obesity and other eating disorders, thereby increasing the importance of understanding 5-HT's role in energy balance. Unfortunately, due to the lack of drugs specific for the many 5-HTergic receptors, studying this role has been difficult. To circumvent this, we propose to use a mouse with a targeted deletion (KO) of the 5-HT2CR to elucidate the action of the 5-HT2CR in the hypothalamic circuitry regulating energy balance. These mice are slightly overweight and have aberrations in energy regulation. Our studies and those of others suggest that the 5-HT2CR is important in the CNS processing of peripheral metabolic cues. This mouse serves as an excellent model to study energy balance regulation. Specific Aim 1 determines the importance of the 5-HT2CR in CNS energy balance circuitry. A battery of metabolic signals will be given to KO and wildtype (WT) mice. They will be examined: (1) anatomically, with fos, to determine CNS sites that require the 5-HT2C receptor for metabolic processing, and (2) physiologically, measuring food intake, oxygen consumption, and hormone levels, to determine whether these mice have normal physiologic responses to metabolic cues, and (3) with manipulations of 5-HT systems in normal mice to see if we can mimic the responses of KO mice with deletions of 5-HT in specific CNS regions. Specific Aim 2 will elucidate interactions of 5-HT2CR and neuropeptide Y (NPY) in the hypothalamus. NPY induced feeding is modulated by 5-HT and by drugs acting at the 5-HT2CR. Three sets of questions will be asked: (1) Do KO mice have normal food intake and SNS responses to icv NPY injection? (2) Is the regulation of NPY at the arcuate nucleus normal in fed and fasted KO mice? (3) What are the projections of hypothalamic 5-HT2CR containing cells? From the experiments of this grant application, we will have an enhanced understanding of the CNS sites important for processing of peripheral metabolic signals, the role of the 5-HT2CR in those sites, and the involvement of 5-HT and the 5-HT2CR in hypothalamic NPY circuitry as it relates to energy balance.